Tetrahydrobiopterin improves diastolic dysfunction by reversing changes in myofilament properties

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Biochemistry

Background:

• Heart failure with preserved ejection fraction (HFpEF) lacks specific treatments due to poorly understood diastolic dysfunction mechanisms.
• Cardiac relaxation may involve nitric oxide (NO) signaling, dependent on tetrahydrobiopterin (BH(4)) and NO synthase (NOS).
• Hypertension can cause diastolic dysfunction, linked to cardiac BH(4) depletion, NOS uncoupling, and myosin binding protein C (MyBP-C) S-glutathionylation.

Purpose of the Study:

• To investigate if BH(4) ameliorates diastolic dysfunction by preventing MyBP-C glutathionylation and restoring myofilament properties.
• To test the hypothesis that BH(4) treatment reverses hypertension-induced diastolic dysfunction and associated molecular changes.

Main Methods:

• Utilized the deoxycorticosterone acetate (DOCA)-salt mouse model of hypertension and diastolic dysfunction.
• Administered BH(4) supplementation to mice post-development of diastolic dysfunction.
• Assessed cardiac function via echocardiography, myofilament properties (force, ATPase activity) using isolated fiber bundles, and MyBP-C glutathionylation via immunoblotting.

Main Results:

• DOCA-salt mice displayed diastolic dysfunction, which was reversed by BH(4) treatment.
• BH(4) restored diastolic sarcomere length and relaxation kinetics (constant τ) to control levels.
• BH(4) treatment normalized altered myofilament calcium sensitivity (pCa50) and ATPase kinetics, while reducing MyBP-C glutathionylation.

Conclusions:

• BH(4) ameliorates diastolic dysfunction in this hypertensive model by reducing MyBP-C S-glutathionylation.
• This mechanism involves reversing impaired cross-bridge turnover kinetics and restoring myofilament properties.
• Findings suggest post-translational modification of myofilament proteins is a key target for modulating cardiac relaxation in diastolic dysfunction.